A Chinese pharmaceutical company employee checks the creation of chloroquine phosphate, an old malaria treatment being touted for COVID-19; the company resumed its production last month after a 15-year break.
FeatureChina via AP Images
When President Donald Trump recently touted the common malaria treatments hydroxychloroquine and chloroquine as potential remedies for coronavirus disease 2019 (COVID-19), he ignited unprecedented demand for the drugs—and set scientists’ teeth on edge. Although the World Health Organization (WHO) agrees the compounds are worth testing more fully on the pandemic coronavirus, few drug or infectious disease experts—not even the president’s own advisers—share his optimism that the drugs could become “one of the biggest game changers in the history of medicine,” as he tweeted. And many are critical of the small French clinical study of just 42 patients that seems to have touched off most of the excitement.
“The president was talking about hope,” Anthony Fauci, director of National Institute of Allergy and Infectious Diseases, said diplomatically at one of the White House briefings where Trump praised the drugs’ potential.
Others are less diplomatic. Darren Dahly, a co-author of one of several critiques of the initial study and a principal statistician at the University College Cork School of Public Health, said it would be “egregious” to recommend treatments for millions of people based on such a small trial, regardless of its quality. “This is insane!” tweeted Gaetan Burgio, an Australian National University expert on drug resistance, noting what he sees as lapses in the 6-day trial, including inconsistent testing of virus levels in the patients.
Related
To Dahly and others, only much larger, better studies such as one WHO has just started can show whether any optimism about the compounds is warranted. “The best way to know whether a medication for COVID-19 is effective is through a high-quality clinical trial,” says Joshua Sharfstein, a vice dean at Johns Hopkins University’s Bloomberg School of Public Health and a former principal deputy Food and Drug Administration commissioner. “Efforts to widely distribute unproven treatments are misguided at best and dangerous at worst.”
Such cautions were buried under an avalanche of demand for hydroxychloroquine, also sold under the brand name Plaquenil, and chloroquine, as doctors rushed to prescribe one or the other for confirmed or possible COVID-19 infections. Among the immediate consequences:
- Shortages of the drug are endangering patients who need it for lupus or rheumatoid arthritis.
- India, a major producer, has banned exports, and some doctors are hoarding both drugs by writing prescriptions for themselves or family members.
- Deaths in Nigeria among people self-treating for apparent COVID-19 were attributed to chloroquine overdoses, and an Arizona man trying to avoid COVID-19 infection died after reportedly self-medicating with a toxic form of chloroquine used to clean fish tanks.
- Brazilian President Jair Bolsonaro, a staunch Trump ally, ordered that nation’s military labs to ramp up production of chloroquine. Panic buying has ensued.
“Here in Brazil even good scientists are backing this, saying we should waive rigor in difficult times,” says Natalia Pasternak Taschner, a microbiologist at the University of São Paulo, São Paulo. “We should be even more rigorous lest we give people false hope and invest [limited] time and money on unwarranted claims.”
Although doctors regard hydroxychloroquine as relatively safe at prescribed doses for short periods, it has been associated with life-threatening cardiac side effects and suicidal behavior. “Given the toxicity of the drug, I’m afraid my government is going to kill people,” Taschner said.
Trump’s initial public remarks on the drug candidates at a 19 March briefing appeared to be based on anecdotal reports from China and the tiny French study, which Vanity Fair reports he learned of after Elon Musk tweeted about it and Fox News amplified the information. In that trial, the Mediterranean Infection University Hospital Institute (IHU) treated 26 COVID-19 patients with hydroxychloroquine alone, or combined with the antibiotic azithromycin. The authors reported “clearance”—no virus present in samples taken by nasopharyngeal swabs—in most of them, but continued infection in most of a 16-person control group of COVID-19 patients. The patients who received both drugs cleared the fastest, the researchers reported in a peer-reviewed paper in the International Journal of Antimicrobial Agents.
HYDROXYCHLOROQUINE & AZITHROMYCIN, taken together, have a real chance to be one of the biggest game changers in the history of medicine. The FDA has moved mountains – Thank You! Hopefully they will BOTH (H works better with A, International Journal of Antimicrobial Agents)…..
— Donald J. Trump (@realDonaldTrump) March 21, 2020
Many scientists have criticized the French trial as riddled with enough methodological flaws to render its findings unreliable or misleading. Biostatisticians from the United Kingdom and Ireland cited a basic failure: Investigators didn’t randomize the groups—essential to ensuring dependable comparisons. They also noted that six of the treated patients were lost to the study, five of whom fared badly—one died, three entered intensive care, and one stopped treatment because of nausea. Yet they were dropped from the analysis, potentially skewing the outcome.
Elisabeth Bik, a scientific integrity consultant, wrote on her blog that for some patients supposedly helped by the treatments, daily tests for the presence of the coronavirus fluctuated between positive and negative, suggesting the virus might have persisted, just below the test’s detection threshold. Investigators should have confirmed viral clearance over two or three consecutive days, she said, particularly because the trial did not keep track of clinical indicators such as fever or shortness of breath. But the viral tests also ended after no more than 6 days total for all patients.
Bik and other researchers have raised questions about other aspects of the paper, including its peer review, noting the submission and acceptance dates suggest it was reviewed in less than 24 hours. One of the paper’s authors is also the journal’s editor-in-chief, which Bik says might be “perceived as a huge conflict of interest.”
“Let’s put our work into running some proper trials, and see if this effect holds up in well-conducted studies,” Dahly says.
One of the French study authors, Didier Raoult, a prominent researcher who heads IHU, released a statement on Monday in response to the criticisms. He said he would treat any COVID-19 patient with a combination of hydroxychloroquine and azithromycin immediately after diagnosis. (“Like any doctor, once a treatment has been shown to be effective, I find it immoral not to administer it. It’s as simple as that,” he told the French newspaper Libération.)
A clearer verdict may come from the WHO megatrial and two other major trials of hydroxychloroquine in different doses that have started at Columbia University and the University of Minnesota. New York Governor Andrew Cuomo announced that the state also will fast-track a trial of hydroxychloroquine plus azithromycin.
Yet evidence from pending studies will certainly lag massive off-label use of chloroquine and hydroxychloroquine given the presidential endorsement. Several major pharma companies announced production of nearly 200 million doses of the two drugs in coming weeks to fight the pandemic.
Vinay Prasad, a hematologist and oncologist at Oregon Health & Science University who studies evidence-based medicine, calls the rush to use the drugs unwise. “In times of epidemic, you want to prioritize manufacturing things that have been proven to work,” many of which are in short supply, he says. “Masks, gowns, ventilators. Have at it. Before ramping up the supply of pills, it’s best to know if the pills work.”